Asbestos is the most important cause of malignant mesothelioma (MM.) in the industrialized world. Because less than 5% of heavily exposed asbestos workers develop MM, additional factors are suspected to render certain individuals more susceptible to asbestos carcinogenicity. Cigarette smoke has been ruled out as a co-factor in MM. Instead, both genetic predisposition and simian virus 40 infections (SV40) have been linked to MM pathogenesis. The central hypothesis of this Program Project is that MM is a malignancy that is mainly caused by asbestos or related fibers (erionite), and that genetic predisposition and SV40 infection make certain individuals more susceptible to asbestos or erionite carcinogenesis. In Project 1, a team of investigators with different expertise led by Dr. Carbone, will try to identify the gene/s that predispose to MM in three villages of Cappadocia, Turkey, where 50% of total deaths are caused by MM. The interaction among genetic predisposition and erionite, a fiber related to crocidolite asbestos which is present in these villages, will also be investigated. Our hypothesis is that this MM-gene/s that is mutated in these Cappadocian families is targeted by asbestos, and possibly by SV40, in sporadic MM in the USA. In Project 2, Dr. Mossman will study if SV40 infection interferes with the mechanisms of asbestos carcinogenesis that she has elucidated throughout the years (ERK pathway and AP-1 activation). In Project 3, Dr. Testa will study how asbestos and SV40 influence the AKT pathway and tumor suppressors (NF-2, p16 and p19) that his work indicates play an important role in MM pathogenesis. Together, these results will provide information on the pathogenesis of MM and on the factors that make certain individuals more susceptible to asbestos/erionite carcinogenesis. This information should allow us to design novel and specific preventive/therapeutic approaches for MM patients. The information developed in this Program Project has general relevance to environmental carcinogenesis because the results will address the hypothesis that genetics and viruses influence the carcinogenesis of mineral fibers. Our multidisciplinary team bridges basic science and clinical expertise. Therefore, our team is perfectly placed to capitalize on the pathogenic information that we will develop during the 5 years of this PO-1 and to take this information to the patient's bed, or preferably, to use this information to reduce the number of those who would become patients.